Dual Oxidase in Airway Epithelial Injury and Inflammation

双氧化酶在气道上皮损伤和炎症中的作用

基本信息

批准号：
9982119
负责人：
ALBERT VAN DER VLIET
金额：
$ 41.02万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-05 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982119
关键词：
Address Affect Allergens Allergic Allergic inflammation Alveolar Macrophages Amphiregulin Anti-Inflammatory Agents Asthma Biology Budgets Cell Line Cell model Cells Chronic Complex Cysteine Development Disease Effector Cell Engineering Enzymes Epidermal Growth Factor Receptor Epithelial Epithelial Cells Epithelium Extracellular Domain Extrinsic asthma Feedback Fibrosis Funding Growth Factor Homologous Gene Hydrogen Peroxide Inflammation Inhalation Injury Interleukin-13 Interleukin-5 Knockout Mice Lung Lymphoid Cell Macrophage Activation Mediating Mediator of activation protein Metaplasia Modification Molecular Mucous Membrane Mucous body substance Mus Myelogenous NADPH Oxidase Oxidases Oxidation-Reduction Oxides Peptides Pharmacology Phosphotransferases Play Process Production Proteins Proteomics Pyroglyphidae Reactive Oxygen Species Receptor Signaling Recombinant Proteins Role Signal Pathway Signal Transduction Skin Structural Models Structure Structure of respiratory epithelium Sulfhydryl Compounds T-Lymphocyte Therapeutic Transforming Growth Factor beta Translating Variant adaptive immune response airborne allergen airway epithelium airway hyperresponsiveness airway remodeling allergic airway inflammation base cell type cellular transduction clinical development cytokine data modeling design epithelial injury experimental study inhibitor/antagonist kinase inhibitor macrophage molecular dynamics mouse Cre recombinase mutant neutrophil new therapeutic target oxidation response src-Family Kinases therapeutic development therapeutic target

项目摘要

PROJECT SUMMARY The NADPH oxidase DUOX1 is prominently expressed within the respiratory epithelium and contributes to innate response mechanisms to injury or other environmental triggers, by generating reactive oxygen species (ROS) and activating redox-dependent signaling pathways. In the present funding cycle of this project, we identified DUOX1 as a critical mediator of innate epithelial responses to allergens, by promoting epithelial secretion of the alarmin IL-33 and subsequent activation of type 2 inflammation. We also observed enhanced epithelial DUOX1 in subjects with allergic asthma, and a critical role for DUOX1 in development of various critical features of house dust mite (HDM)-induced allergic airway inflammation in mice, such as mucus metaplasia, subepithelial fibrosis, and airway hyperresponsiveness. These actions of DUOX1 were largely related to redox-dependent activation of Src family kinases and epidermal growth factor receptor (EGFR) signaling, both well-recognized factors in allergic inflammation and airway remodeling, in part by mediating cysteine oxidation within these kinases. During these studies, we noted that DUOX1 is not only operative within the airway epithelium, but is also present in non- epithelial cell types such as alveolar macrophages, and appears to be involved in macrophage polarization and IL-33-mediated pro-fibrotic mediators such as IL-13 and TGF-β that are involved in airway remodeling. The first aim of this renewal application is to delineate the cell-specific actions of DUOX1 on various aspects of HDM- induced allergic inflammation and remodeling, specifically focusing on a potential role for DUOX1 in alternative neutrophil (N2) polarization or macrophage (M2) activation. Aim 2 is to identify redox-sensitive targets of DUOX1 and characterize the molecular mechanisms by DUOX1-dependent cysteine oxidation regulates the enzymatic function of Src, using molecular dynamics simulations and experimental studies with various cysteine variants. Finally, based on previous findings that thiol-reactive electrophiles can inhibit DUOX1 activation, aim 3 will be to develop peptide-based cysteine-targeted approaches to pharmacologically inhibit DUOX1 activity, thus filling an unmet need for DUOX1-selective inhibitors that may be used for clinical development in treatment of severe asthma.

项目概要 NADPH 氧化酶 DUOX1 在呼吸道上皮细胞中显着表达，有助于先天性通过产生活性氧 (ROS) 对损伤或其他环境触发因素的反应机制在该项目当前的资助周期中，我们确定了激活氧化还原依赖性信号通路。 DUOX1 作为先天上皮对过敏原反应的关键介质，通过促进上皮分泌 Alarmin IL-33 和随后的 2 型炎症激活我们还观察到上皮 DUOX1 增强。在过敏性哮喘受试者中，DUOX1 在房屋各种关键特征的发展中发挥着关键作用尘螨（HDM）引起的小鼠过敏性气道炎症，如粘液化生、上皮下纤维化、 DUOX1 的这些作用很大程度上与氧化还原依赖性激活有关。 Src 家族激酶和表皮生长因子受体 (EGFR) 信号传导，这两个因素在过敏性炎症和气道重塑，部分是通过介导这些激酶内的半胱氨酸氧化来实现的。在这些研究中，我们注意到 DUOX1 不仅在气道上皮内发挥作用，而且也存在于非呼吸道上皮细胞中。上皮细胞类型，例如肺泡巨噬细胞，并且似乎参与巨噬细胞极化和 IL-33 介导的促纤维化介质，例如参与气道重塑的 IL-13 和 TGF-β。该更新申请的目的是描绘 DUOX1 对 HDM 各个方面的细胞特异性作用过敏引起的炎症和重塑，特别关注 DUOX1 在替代疗法中的潜在作用中性粒细胞 (N2) 极化或巨噬细胞 (M2) 激活目标 2 是识别 DUOX1 的氧化还原敏感靶标。并表征了通过DUOX1依赖性半胱氨酸氧化调节酶促反应的分子机制 Src 的函数，使用分子动力学模拟和各种半胱氨酸变体的实验研究。最后，基于先前的发现，硫醇反应性亲电子试剂可以抑制 DUOX1 激活，目标 3 将是开发基于肽的半胱氨酸靶向方法来药理学抑制 DUOX1 活性，从而填补对 DUOX1 选择性抑制剂的未满足需求可用于治疗严重的临床开发哮喘。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protein alkylation by the α,β-unsaturated aldehyde acrolein. A reversible mechanism of electrophile signaling?

蛋白质由α,β-不饱和醛丙烯醛烷基化。

DOI：
发表时间：
2013-11-29
期刊：
影响因子：
3.5
作者：
Randall, Matthew J;Hristova, Milena;van der Vliet, Albert
通讯作者：
van der Vliet, Albert

Redox regulation of tyrosine kinase signalling: more than meets the eye.

酪氨酸激酶信号传导的氧化还原调节：比表面上看到的更复杂。

DOI：
发表时间：
2020-02-01
期刊：
影响因子：
0
作者：
Dustin, Christopher M;Heppner, David E;Lin, Miao;van der Vliet, Albert
通讯作者：
van der Vliet, Albert

Purinergic signaling in wound healing and airway remodeling.

伤口愈合和气道重塑中的嘌呤能信号传导。

DOI：
10.1007/978-94-007-1217-1_6
发表时间：
2024-09-13
期刊：
Sub-cellular biochemistry
影响因子：
0
作者：
A. van der Vliet;Peter F. Bove
通讯作者：
Peter F. Bove

Acrolein-induced activation of mitogen-activated protein kinase signaling is mediated by alkylation of thioredoxin reductase and thioredoxin 1.

丙烯醛诱导的丝裂原激活蛋白激酶信号传导的激活是通过硫氧还蛋白还原酶和硫氧还蛋白 1 的烷基化介导的。

DOI：
发表时间：
2013
期刊：
影响因子：
11.4
作者：
Randall, Matthew J;Spiess, Page C;Hristova, Milena;Hondal, Robert J;van der Vliet, Albert
通讯作者：
van der Vliet, Albert

The NADPH Oxidases DUOX1 and NOX2 Play Distinct Roles in Redox Regulation of Epidermal Growth Factor Receptor Signaling.

NADPH 氧化酶 DUOX1 和 NOX2 在表皮生长因子受体信号传导的氧化还原调节中发挥独特的作用。

DOI：
发表时间：
2016
期刊：
影响因子：
0
作者：
Heppner, David E;Hristova, Milena;Dustin, Christopher M;Danyal, Karamatullah;Habibovic, Aida;van der Vliet, Albert
通讯作者：
van der Vliet, Albert